PROJECT SUMMARY: ABSTRACT I (the candidate) am an academic faculty in adult epileptology, with strong clinical training and a PhD doctorate in applied mathematics from Oxford University where I was a Rhodes scholar. I have a career commitment to patient-oriented research, and have achieved preliminary success in applying my skills to important scientific problems in epilepsy. In 2007 I was awarded a Milken Family Foundation Early Career Award from the American Epilepsy Society that enabled me to commence work on a promising and novel imaging technique (oxygen-enhanced MRI; OE-MRI) for the diagnosis of focal epilepsy. In 2010, I was co-PI on a seed grant from the Center for Clinical and Translational Sciences at UTHSC-Houston to explore OE-MRI under conditions of functional activation. These small awards have resulted in intriguing and promising pilot data. I now wish to protect my time to build the solid foundation of a long-term research career in epilepsy neuroimaging, under the mentorship of senior established investigators. My research project will advance the application of OE-MRI (achieved by subjects breathing 100% oxygen during scanning) for better anatomical diagnosis of focal epilepsy, and for noninvasive identification of eloquent cortex. Identifying an imaging lesion remains crucial in the workup of focal epilepsy patients, particularly those for whom epilepsy surgery is planned. Yet upto 30% of all refractory focal epilepsy patients have normal imaging, even with the most advanced techniques in routine clinical use (high-field strength MRI and PET). In recently published pilot studies (Kalamangalam et al (2011), Epilepsy Research ? manuscript appended), I have demonstrated that OE produces a robust and diagnostically useful contrast MRI signal that achieves diagnosis and lateralization of temporal lobe epilepsy with good sensitivity and perfect specificity. In particular, OE can be lateralizing in the complete absence of MRI or PET abnormalities. I wish to extend these exciting findings on a longer term prospective basis to larger patient groups with both temporal lobe and neocortical epilepsies (Specific Aim I). An important, though different, concern in epilepsy surgery patients is the precise localization of eloquent cortex (mainly language, motor function and memory laterality). The gold standard tests for all these modalities are invasive (electrical stimulation mapping for language and motor, and the Wada test for memory). However, the strong contrast signal produced by 100% oxygen suggested that classical fMRI methods applied to detect eloquent cortex would be more informative under OE conditions, leading to improved nonivasive estimates of eloquent cortical areas than has been possible hitherto. My preliminary data with normal subjects indicates that this premise may be true. I wish to explore these intriguing results on a long-term prospective basis in our epilepsy surgery patients (Specific Aim II). The training and career development aspects of the award will comprise a thorough grounding in modern neuroimaging, focusing on MRI and fMRI, experiment design, data analysis and interpretation. I will also complete training in general clinical research methods. Training will be achieved with mix of didactic sessions with my primary mentor, Dr Ponnada A Narayana, an MRI scientist of international standing, and attendance at national training workshops. I will also complete selected courses in advanced neuroscience offered at UTHSC?s graduate school. I will also receive structured training in biostatistics, translational research and epidemiologic methods offered by the Center for Clinical Research and Evidenced- Based Medicine, which will be supervised by my co-mentor Dr James A Ferrendelli, our former Chairman and past President of the American Epilepsy Society. The institutional facilities and infrastructure available to me via the MRI Research Division and the Center for Clinical and Translational Sciences at UTHSC-Houston are the ideal setting in which to accomplish my goals. Our epilepsy clinical service ? comprising the outpatient environment of UT Physicians and the inpatient Epilepsy Monitoring Unit of Memorial Hermann Hospital ? follows >1500 patients yearly, providing a sufficient patient population base for recruitment of study subjects for my research. My department Chair, Dr James Grotta, guarantees 75% protected time for my research, in addition to providing any secretarial and administrative support required. I also have a supportive cohort of faculty colleagues at all career stages, including senior NIH-funded clinical researchers. At the end of the K23 award period I will be ideally placed to apply for an NIH RO1 grant to pursue an independent clinical research career in epilepsy neuroimaging. In doing so, I will be firmly on the path of my long-term goal of a clinical research career in academic epileptology.